Circadian entrainment and molecular mechanisms of protein aggregation

Living organisms used zeitgebers to synchronize/entrain their biological clocks (Pittendrigh, 1993). This synchronization specifies expression of genes and proteins to specific times of a day. Disruption of circadian entrainment has been reported to increase susceptibility to several diseases including cardiovascular diseases, cancer, dementia-associated disorders, metabolic disorders, etc. (Ferrell and Chiang, 2015; Musiek, 2015; Stevens et al., 2014), possibly due to disruption of phase specific molecular expression patterns. In the present study, we investigated how temperature, a zeitgeber of the circadian clock, impacts a model of poly glutamine aggregation diseases. Clinical studies showed that patients with these diseases have a lower amplitude endogenous temperature rhythm (Pierangeli et al., 1997). Furthermore, endogenous temperature rhythms in healthy mice are sufficient to localize Heat Shock Factor-1 (HSF-1), a transcription factor that regulates expression of numerous heat shock genes, in the nucleus (Reinke et al., 2008). Heat shock proteins are suppressors of protein aggregation. We hypothesized that temperature entrainment might directly impact protein aggregation via heat shock protein expression. To test this hypothesis, a C. elegans strain carrying a transgene expression of 35 glutamines (polyQ) was incubated in either constant temperature or 24 h temperature cycles. The aggregation of polyQ was significantly reduced in temperature cycles compared to constant conditions. We further investigated the composition of protein aggregates in the two temperature conditions, revealing greater complexity of aggregates formed in temperature cycles. We also investigated the expression of a subset of genes encoding heat shock proteins. We found that heat shock genes encoding proteins that have chaperone function are rhythmically expressed in temperature cycles. Neurodegenerative pathologies can invoke metabolic stress. Unpublished data (Olmedo, Geibel, Merrow) shows that metabolic stress impedes development. We investigated the rate of development in poly glutamine transgenic worms. Our data suggests that developmental timing is delayed in polyQ worms at all temperature conditions. The major finding of this work is that zeitgebers of circadian clock can decrease the load of protein aggregates in poly-glutamine model, apparently by structuring the expression of their suppressors.Lebende Organismen brauchen Zeitgeber, um ihre innere Uhr zu synchronisieren (Pittendrigh, 1993). Diese Synchronisation konzentriert die Expression von Genen und Proteinen auf bestimmte Tageszeiten. Eine Störung des zirkadianen Entrainments erhöht die Anfälligkeit für etliche Krankheiten, unter anderem Herz-Kreislauferkrankungen, Krebs, Demenz-assoziierte Störungen, Stoffwechselkrank-heiten und viele weitere (Ferrell and Chiang, 2015; Musiek, 2015; Stevens et al., 2014). Ursache hierfür ist möglicherweise eine Störung des phasenspezifischen molekularen Expressionsmusters. Einer der bekannten Zeitgeber für die innere Uhr ist Temperatur. In der vorliegenden Studie haben wir untersucht, welchen Einfluss diese auf ein Modell für Polyglutamin-Aggregationserkrankungen hat. Klinische Studien haben gezeigt, dass der zirkadiane Körpertemperaturrhythmus von Patienten mit solchen Krankheiten eine niedrigere Amplitude hat (Pierangeli et al., 1997). Bei gesunden Mäusen reichen endogene Temperaturzyklen aus, um Heat Shock-Faktor 1 (HSF-1) in den Zellkern zu lokalisieren (Reinke et al., 2008). HSF-1 ist ein Transkriptionsfaktor, der eine Vielzahl von Hitzeschockgenen reguliert. Diese sind wiederum Suppressoren der Proteinaggregation. Wir nehmen an, dass das Entrainment mit Temperaturzyklen durch die Expression von Hitzeschockproteinen einen direkten Einfluss auf die Proteinaggregation hat. Um diese Hypothese zu untersuchen, wurde ein transgener Stamm des Fadenwurms C. elegans verwendet, welcher eine Mutation aufweist, die zur Expression von 35 Glutaminresten (PolyQ) führt. Die Würmer wurden entweder in konstanter Temperatur oder in Temperaturzyklen gehalten. Die PolyQ-Aggregation in Temperaturzyklen war im Vergleich zu konstanten Bedingungen signifikant geringer. Ferner untersuchten wir die Zusammensetzung der Aggregate in den beiden Temperaturregimes, wobei sich bei den Aggregaten aus den Temperaturzyklen eine deutlich größere Komplexität zeigte. Als Nächstes wurde die Expression einiger ausgewählter Gene untersucht, welche für Hitzeschockproteine kodieren. Dabei haben wir herausgefunden, dass die Hitzeschockgene, die für Proteine mit Chaperon-Funktion kodieren, in Temperaturzyklen rhythmisch exprimiert werden. Neurodegenerative Erkrankungen können zu metabolischer Belastung führen. Noch nicht veröffentlichte Daten aus unserem Labor (Olmedo, Geibel, Merrow) zeigen, dass dieser Stoffwechselstress die Entwicklung behindern kann. Wir haben daher die Geschwindigkeit der Entwicklung in transgenen PolyQ-Würmern untersucht. Unsere Daten deuten darauf hin, dass die Entwicklung dieser Tiere bei allen bisher untersuchten Temperaturen verzögert ist. Die Haupterkenntnis der vorliegenden Arbeit ist, dass physiologische Zeitgeberzyklen - scheinbar durch die zeitlich strukturierte Expression von Suppressoren - die Menge an Proteinaggregaten in einem Polyglutamin-Modell verringern können.Deutsche Übersetzung des Titels: Zirkadianes Entrainment und molekulare Mechanismen von Protein-Aggregatio

Circadian entrainment and molecular mechanisms of protein aggregation

Living organisms used zeitgebers to synchronize/entrain their biological clocks (Pittendrigh, 1993). This synchronization specifies expression of genes and proteins to specific times of a day. Disruption of circadian entrainment has been reported to increase susceptibility to several diseases including cardiovascular diseases, cancer, dementia-associated disorders, metabolic disorders, etc. (Ferrell and Chiang, 2015; Musiek, 2015; Stevens et al., 2014), possibly due to disruption of phase specific molecular expression patterns. In the present study, we investigated how temperature, a zeitgeber of the circadian clock, impacts a model of poly glutamine aggregation diseases. Clinical studies showed that patients with these diseases have a lower amplitude endogenous temperature rhythm (Pierangeli et al., 1997). Furthermore, endogenous temperature rhythms in healthy mice are sufficient to localize Heat Shock Factor-1 (HSF-1), a transcription factor that regulates expression of numerous heat shock genes, in the nucleus (Reinke et al., 2008). Heat shock proteins are suppressors of protein aggregation. We hypothesized that temperature entrainment might directly impact protein aggregation via heat shock protein expression. To test this hypothesis, a C. elegans strain carrying a transgene expression of 35 glutamines (polyQ) was incubated in either constant temperature or 24 h temperature cycles. The aggregation of polyQ was significantly reduced in temperature cycles compared to constant conditions. We further investigated the composition of protein aggregates in the two temperature conditions, revealing greater complexity of aggregates formed in temperature cycles. We also investigated the expression of a subset of genes encoding heat shock proteins. We found that heat shock genes encoding proteins that have chaperone function are rhythmically expressed in temperature cycles. Neurodegenerative pathologies can invoke metabolic stress. Unpublished data (Olmedo, Geibel, Merrow) shows that metabolic stress impedes development. We investigated the rate of development in poly glutamine transgenic worms. Our data suggests that developmental timing is delayed in polyQ worms at all temperature conditions. The major finding of this work is that zeitgebers of circadian clock can decrease the load of protein aggregates in poly-glutamine model, apparently by structuring the expression of their suppressors.Lebende Organismen brauchen Zeitgeber, um ihre innere Uhr zu synchronisieren (Pittendrigh, 1993). Diese Synchronisation konzentriert die Expression von Genen und Proteinen auf bestimmte Tageszeiten. Eine Störung des zirkadianen Entrainments erhöht die Anfälligkeit für etliche Krankheiten, unter anderem Herz-Kreislauferkrankungen, Krebs, Demenz-assoziierte Störungen, Stoffwechselkrank-heiten und viele weitere (Ferrell and Chiang, 2015; Musiek, 2015; Stevens et al., 2014). Ursache hierfür ist möglicherweise eine Störung des phasenspezifischen molekularen Expressionsmusters. Einer der bekannten Zeitgeber für die innere Uhr ist Temperatur. In der vorliegenden Studie haben wir untersucht, welchen Einfluss diese auf ein Modell für Polyglutamin-Aggregationserkrankungen hat. Klinische Studien haben gezeigt, dass der zirkadiane Körpertemperaturrhythmus von Patienten mit solchen Krankheiten eine niedrigere Amplitude hat (Pierangeli et al., 1997). Bei gesunden Mäusen reichen endogene Temperaturzyklen aus, um Heat Shock-Faktor 1 (HSF-1) in den Zellkern zu lokalisieren (Reinke et al., 2008). HSF-1 ist ein Transkriptionsfaktor, der eine Vielzahl von Hitzeschockgenen reguliert. Diese sind wiederum Suppressoren der Proteinaggregation. Wir nehmen an, dass das Entrainment mit Temperaturzyklen durch die Expression von Hitzeschockproteinen einen direkten Einfluss auf die Proteinaggregation hat. Um diese Hypothese zu untersuchen, wurde ein transgener Stamm des Fadenwurms C. elegans verwendet, welcher eine Mutation aufweist, die zur Expression von 35 Glutaminresten (PolyQ) führt. Die Würmer wurden entweder in konstanter Temperatur oder in Temperaturzyklen gehalten. Die PolyQ-Aggregation in Temperaturzyklen war im Vergleich zu konstanten Bedingungen signifikant geringer. Ferner untersuchten wir die Zusammensetzung der Aggregate in den beiden Temperaturregimes, wobei sich bei den Aggregaten aus den Temperaturzyklen eine deutlich größere Komplexität zeigte. Als Nächstes wurde die Expression einiger ausgewählter Gene untersucht, welche für Hitzeschockproteine kodieren. Dabei haben wir herausgefunden, dass die Hitzeschockgene, die für Proteine mit Chaperon-Funktion kodieren, in Temperaturzyklen rhythmisch exprimiert werden. Neurodegenerative Erkrankungen können zu metabolischer Belastung führen. Noch nicht veröffentlichte Daten aus unserem Labor (Olmedo, Geibel, Merrow) zeigen, dass dieser Stoffwechselstress die Entwicklung behindern kann. Wir haben daher die Geschwindigkeit der Entwicklung in transgenen PolyQ-Würmern untersucht. Unsere Daten deuten darauf hin, dass die Entwicklung dieser Tiere bei allen bisher untersuchten Temperaturen verzögert ist. Die Haupterkenntnis der vorliegenden Arbeit ist, dass physiologische Zeitgeberzyklen - scheinbar durch die zeitlich strukturierte Expression von Suppressoren - die Menge an Proteinaggregaten in einem Polyglutamin-Modell verringern können.Deutsche Übersetzung des Titels: Zirkadianes Entrainment und molekulare Mechanismen von Protein-Aggregatio

The impact of shift-work light conditions on tissue-specific circadian rhythms of canonical clock genes: insights from a mouse model study [version 2; peer review: 2 approved]

Background: The natural day-night cycle synchronizes our circadian rhythms, but modern work practices like night shifts disrupt this pattern, leading to increased exposure to nighttime light. This exposure is linked to various health issues. While some studies have explored the effects of night shifts on human circadian rhythms, there is limited research on the consequences of long-term exposure to shift-work light conditions. Rodents can provide valuable insights into these effects. This study aimed to examine how short- or long-term exposure to rotating shifts and chronic jetlag affects the core circadian oscillators in the liver and skin of mammals. Methods: C57BL/6J male mice were subjected to simulated shift-work light conditions, including short-term or long-term rotating shifts and chronic jet-lag conditions. Liver and skin samples were collected every four hours over a 24-hour period on the second day of constant darkness. RNA was extracted and qRT-PCR analysis was conducted to measure the circadian gene expression in liver and skin tissues. Circadian rhythm analysis using CircaCompare compared the control group to mice exposed to shift-work light conditions. Results: The liver's circadian clock is significantly altered in mice under long-term rotating shift conditions, with a lesser but still noticeable impact in mice experiencing chronic jetlag. However, short-term rotating shift conditions do not significantly affect the liver's circadian clock. Conversely, all three simulated shift conditions affect the skin's circadian clock, indicating that the skin clock is more sensitive to shift-work light conditions than the liver clock. Compared to the liver, the skin's circadian clock is greatly affected by long-term rotating shift conditions. Conclusions: The study findings indicate more pronounced disturbances in the canonical clock genes of the skin compared to the liver under simulated shift-work light conditions. These results suggest that the skin clock is more vulnerable to the effects of shift-work

The impact of shift-work light conditions on tissue-specific circadian rhythms of canonical clock genes: insights from a mouse model study [version 3; peer review: 2 approved]

Background: The natural day-night cycle synchronizes our circadian rhythms, but modern work practices like night shifts disrupt this pattern, leading to increased exposure to nighttime light. This exposure is linked to various health issues. While some studies have explored the effects of night shifts on human circadian rhythms, there is limited research on the consequences of long-term exposure to shift-work light conditions. Rodents can provide valuable insights into these effects. This study aimed to examine how short- or long-term exposure to rotating shifts and chronic jetlag affects the core circadian oscillators in the liver and skin of mammals. Methods: C57BL/6J male mice were subjected to simulated shift-work light conditions, including short-term or long-term rotating shifts and chronic jet-lag conditions. Liver and skin samples were collected every four hours over a 24-hour period on the second day of constant darkness. RNA was extracted and qRT-PCR analysis was conducted to measure the circadian gene expression in liver and skin tissues. Circadian rhythm analysis using CircaCompare compared the control group to mice exposed to shift-work light conditions. Results: The liver's circadian clock is significantly altered in mice under long-term rotating shift conditions, with a lesser but still noticeable impact in mice experiencing chronic jetlag. However, short-term rotating shift conditions do not significantly affect the liver's circadian clock. Conversely, all three simulated shift conditions affect the skin's circadian clock, indicating that the skin clock is more sensitive to shift-work light conditions than the liver clock. Compared to the liver, the skin's circadian clock is greatly affected by long-term rotating shift conditions. Conclusions: The study findings indicate more pronounced disturbances in the canonical clock genes of the skin compared to the liver under simulated shift-work light conditions. These results suggest that the skin clock is more vulnerable to the effects of shift-work

1825P Prevalence of cancer among e-cigarette smokers compared to non-smokers: A retrospective cross-sectional survey study of NHANES-CDC

Background: Current e-cigarette use has been rising, assuming as a safe alternative to traditional smoking. Therefore, we aim to evaluate the prevalence of cancer and types of cancers amongst e-cigarette and traditional smokers. Methods: A retrospective cross-sectional survey study was performed using NHANES (National Health And Nutrition Examination Survey) database from 2015 to 2018. History of cancer (MCQ220), type of cancers (MCQ230a), and smoking status (E-cigarette: SMQ900 or SMQ905 and Traditional smoking: SMQ020) were identified. Univariate and multivariable logistic regression analysis was performed to find out prevalence and association between e-cigarette smoking and cancer. We have excluded respondents with dual smoking. Results: Out of 154,856 participants, 7756 (5.01%) were e-cigarette users, 48625 (31.4%) were traditional smokers, 98475 (63.59%) were non-smokers. Females (49 vs 38%), Mexican Americans (20 vs 13%), high annual household income (\u3e$100,000: 23 vs 15%) were having a higher prevalence of e-cigarette smoking in comparison with traditional smoking. (p\u3c0.0001) Prevalence of cancer (any type) was 11.61%. Cancer prevalence was higher amongst traditional smokers in comparison with e-cigarette smokers. (16.77 vs 2.32%; p\u3c0.0001) E-cigarette smokers were younger at the diagnosis of 1st cancer in comparison with traditional smokers. (median: 45 vs 63-years; p\u3c0.0001) Cervical (21.99 vs 2.01%), thyroid (10.64 vs 2.45%), leukemias (8.51 vs 1.08%), and breast (12.06 vs 12.01%) cancers were more prevalent amongst e-cigarette smokers in comparison to traditional smokers. (p\u3c0.0001) In adjusted multivariable regression analysis, e-cigarette smokers [aOR: 1.3 (95%CI: 1.32-1.33); p\u3c0.0001] and traditional smokers [1.6 (1.64-1.65); p\u3c0.0001] were having higher odds of prevalence of cancer in comparison with non-smoker. Conclusions: E-cigarette smokers had an early age of cancer onset and higher odds of cancer prevalence. Females had higher use of e-cigarette and cervical, thyroid, and breast cancers were prevalent amongst e-cigarette users. More prospective studies should be planned to mitigate the risk and before considering e-cigarette as a safe alternative to traditional smoking

Про сутність і структуру процесів взаємодії суб’єктів інноваційної діяльності

Сутність взаємодії суб’єктів інноваційної діяльності у статті визначається з урахуванням трансформації творчого зерна у суспільне надбання, що пов’язане з узгодженням економічних інтересів на всіх рівнях НІС; наводиться секторальна структура НІС за функціональним критерієм та критерієм, що враховує інноваційну активність економічних суб’єктів.In the article essence of co-operation of actors of innovative activity is determined taking into account transformation of creative corn in public property which is related to the concordance of economic interests at all levels of NIS; a sector structure of NIS is pointed after a functional criterion and criterion which takes into account innovative activity of economic actors

COVID-19 Infection and Guillain-Barre Syndrome: A Case Series

The coronavirus disease 2019 (COVID-19) pandemic brought about an unprecedented time. Multiple systemic complications have been recognized with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) as it can do much more than affect the respiratory system. One of the intriguing neurological complications is Guillain-Barre syndrome (GBS). We reviewed three cases in which patients presented with GBS following COVID-19 infection. All three cases had positive lumbar puncture results with albumino-cytological dissociation. Each patient was treated with plasmapheresis and improved clinically. Although an exact causal relationship between COVID-19 and GBS cannot be drawn from this case series alone, it signifies the importance of this complication. It warrants further studies to establish the causal relationship. One should have a high suspicion for acute inflammatory demyelinating polyneuropathy (AIDP) in patients presenting with acute onset of ascending weakness following COVID-19 infection

Biochemical and molecular studies of 132 patients with galactosemia

We evaluated 132 galactosemia patients for the Q188R (glutamine-188 to arginine) mutation in the human galactose-1-phosphate uridyltransferase (GALT) gene and for GALT activity in their hemolysates by a sensitive radioisotopic method. In those without any detectable GALT activity (GG), the Q188R mutation constituted 67% of the alleles. In patients with detectable GALT activity (GV), only 16% of the alleles were accounted for by Q188R. In all patients who were homozygous for the Q188R mutation, no erythrocyte GALT activity could be demonstrated. There was an extensive variation in the amount of detectable GALT activity ranging from 0.1% to 5% of the normal values among the GV patients. There was a difference in the frequency of Q188R mutation in the GALT alleles among patients belonging to different racial and ethnic groups. In Caucasian and Hispanic patients, the frequency was not far different (64% and 58%, respectively). On the other hand, only 12% of the GALT alleles with Q188R were found in African-American patients.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/47637/1/439_2004_Article_BF00201593.pd